Pyrazoloindenone azines



United States Patent 2,969,374 PYRAZOLOINDEN ONE AZINES Bernard Loev, Broomall, Pa., and William A. Mosher,

Newark, Del., assignors to Smith Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Filed Nov. 6, 1959, Ser. No. 851,262

8 Claims. (Cl. 260-310) FORMULA I R represents alkyl having 1 to 6 carbon atoms inclusive, alkenyl having 2 to 6 carbon atoms inclusive, aralkyl having 7 to 8 carbon atoms such as benzyl or phenethyl,

cycloalkyl having 3 to 6 carbon atoms inclusive or cycloalkenyl having 4 to 6 carbon atoms inclusive;

R represents hydrogen, alkyl having 1 to 4 carbon atoms inclusive or trifluoromethyl;

R represents hydrogen, alkyl having 1 to 4 carbon atoms inclusive, trifiuoromethyl, cycloalkyl having 3 to 6 carbon atoms inclusive, phenyl, halophenyl, lower alkoxyphenyl, lower alkylphenyl, aminophenyl or aralkyl having 7 to 8 carbon atoms such as benzyl or phenethyl.

R R R and R represent hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, nitro, amino or trifluoro-' methyl, three of said substituents, R R R and R being hydrogen when one is trifluoromethyl; and

R represents hydrogen, lower alkyl, aralkyl having 7 to 8 carbon atoms such as benzyl or phenethyl or acyl of less than 9 carbon atoms such as benzene-sulfonyl, benzoyl, lower alkanoyl, for instance acetyl or propionyl or lower alkyloxycarbonyl such as carbethoxy or carbomethoxy.

Preferred compounds of this invention are represented by the following fundamental formula:

FORMULA II N I w when:

R is hydrogen, chloro or trifluoromethyl; and

R R R and R are as defined in Formula I.

Preferred and advantageous compounds are those of Formula II in which R is alkyl having 1 to 6 carbon atoms inclusive, alkenyl having 2 to 6 carbon atoms inclusive, or cycloalkyl having 3 to 6 carbon atoms inclusive; R and R are methyl; R is hydrogen and R is as defined in Formula II.

The terms lower alkyl, lower alkoxy or lower alkanoyl are used herein to indicate moieties with not more than 4 carbon atoms preferably 1 or 2 carbon atoms.

Whenever basic or acidic producing moieties are present in the compounds of this invention the corresponding nontoxic, chemically stable and pharmaceutically acceptable salts are included in this invention such as the acid addition salts of an amino substituent. V

The pyrazoloindenone azines of this invention are prepared from the corresponding 3-substituted-pyrazolo [3,4-a]inden 4(1H)-one, hydrazones. These starting materials in which there is a trifluoromethyl substituent on the benzene nucleus are described and their preparation outlined in our copending application, Serial No. 848,927, filed October 27, 1959. Other pyrazolo[3,4-a] inden-4(lH)-one, hydrazone starting materials are prepared in similar fashion. Briefly, these compounds are prepared from 2-acyl-l,3-indandiones, which are either known to the art or are conveniently prepared by condensation of a methyl ketone with a dimethyl or diethyl phthalate frequently in an aromatic solvent such as benzene or toluene with an alkaline condensing agent such as sodium methoxide, sodium ethoxide, sodium hydride or sodium hydroxide. These 2-acyl-1,3-indandiones are reacted with various molar equivalents of hydrazine. For instance, substantially equivalent molar quantities of the 2-acyl-l,3-indandione and hydrazine are reacted at elevated temperatures, such as from about 40 C. to C., for a reaction period of from about 30 minutes to 24 hours in a solvent in which the reactants are substantially soluble and with which no chemical reaction occurs, preferably a lower alcohol such as methanol or ethanol to give the 3-substituted-pyrazolo[3,4-a]-inden 4(1H)-one intermediates.

When a compound in which R is lower alkyl, aralkyl or acyl is desired, the 3-substituted-pyrazolo-[3,4-a]inden- 4(lH),-one intermediate is reacted with a basic reagent, preferably an alkali metal or its hydroxide, amide, carbonate or hydride to form the N-metal salt, for instance the preferred sodium, potassium or lithium derivative at the l-position. This N-metal derivative is then reacted with a reactive alkyl, aralkyl or acyl halide to give the l-substituted intermediates.

The 3-substituted-pyrazolo[3,4-a]-inden -4- (1H)-one, hydrazones are prepared by reacting the ketone intermediates with at least one molar equivalent of hydrazine at from 30 minutes to 72 hours under reaction conditions much like those described hereabove for the formation of the pyrazoloindenones.

Alternatively, and preferably, when R is hydrogen, the pyrazolo[3,4-a]inden-4(1H)-one, hydrazones which are starting materials for the preparation of the azines of this invention, are prepared by the one-step reaction of 2-acyl-l,3-indandione with at least two moles of hydrazine, under reaction conditions similar to those under which the pyrazoloindenones are formed, to give the desired hydrazones directly.

When 2-acyl-l,3-indandione compounds unsymmetrically substituted in the benzene ring are cyclized as described above, varying amounts of the two possible pyrazoloindenone isomers are obtained. These isomers are separated by fractional crystallization of the hydrazone or azine derivatives from a suitable solvent such as a lower alcohol, for example aqueous ethanol.

Also there is some possibility that the l-substituents may be on the 2position in certain cases. The compounds which are the objects of this invention, however, have been named in the mostlogical manner known at this time and all isomers thereof are included in this invention.

The pyrazoloindenone aziues of this invention are prepared by reacting the pyrazolo[3,4-a]-inden-4-(1H)-one, hydrazone starting materials with a ketone of the formula R -COR in which R and R are as defined in Formula I. The reaction is carried out in the presence of acid, preferably a mineral acid such as hydrochloric or sulfuric acid, and with at least one molar equivalent of the ketone preferably an excess. Optionally the reaction is run in a solvent in which the reactants are substantially soluble and with which no chemical reaction occurs such as ether or a lower alcohol for example methanol or ethanol. The reaction is carried out at temperatures of less than about 50 (2., preferably at room temperature, for a reaction period of about 1-0 to 30 minutes. The reaction mixture is worked up by concentrating and then recrystallizing the residue from a suitable solvent, for instance aqueous alcohol such as aqueous methanol or ethanol, to give the pyrazoloindenone azines of this invention. Alternatively the reaction mixture is worked up by diluting with water and isolating the azine by filtration.

The preparation of the azines of this invention in which R; and R are hydrogen is advantageously carried out by reacting the hydrazone starting material with formaldehyde-formic acid in a suitable solvent such as a lower alcohol, for example methanol or ethanol. The reaction is carried out under conditions substantially similar to those described hereabove to obtain the pyrazoloindenone, formaldehyde azine.

It will be apparent to one skilled in the art that many variations of this invention can be practical. The following examples are designed to teach fully the preparation of the compounds of this invention and 'are not meant to limit the scope of this invention.

Example 1 A mixture of 97.0 g. of dimethyl 'phthala'te and 43.0 g. of 3-methyl-2-butanone is treated with 28.5 g. of sodium methoxide. After adding 300 ml. of toluene the mixture is heated on a steam bath for ten hours. Evaporating the volatiles in vacuo, dissolving the residue in water, acidifying the aqueous solution with concentrated hydrochloric acid and extracting with ether gives, upon evaporation of the ether extracts, 2-isobutyryl-1,3-indandione.

Hydrazine hydrate (10.1 g.) and Z-isobutyryl-LS-indandione (43.2 g.) are refluxed for four hours in 400 ml. of ethanol. The solution is cooled and diluted with l 1. of cold water. The resulting solid is separated to give 3-isopropylpyrazolo 3,4-a] inden-4( 1H -one.

A mixture of 21.2 g. of this ketone, 3.2 g. of hydrazine and 250 ml. of ethanol is heated at reflux for 36 hours. Cooling separates 3 -isopropylpyrazolo[3,4-a]'inden-4- (1H)-one, hydrazone.

To 5.5 g. of this hydrazone in 30 ml. of acetone is added 3 drops of concentrated hydrochloric acid. The solution becomes intense yellow in color. Removal of the excess acetone in vacuo at ambient temperature and recrystallization of the residue from aqueous methanol gives 3-iso ropylpyrazolo 3 .4-a] inden-4 1H) -one, acetone azine, M.P 170-171 C.

Example 2 A mixture of 5.5 g. of 3-isopropylpyrazol0[3;4-a] inden-4(lH)-one, prepared as in Example 1, in 150 ml. of aqueous sodium hydroxide is heated at 80 C. for three minutes. The filtered solution is cooled to give the sodium salt.

The sodium salt prepared above (4.0 g.) is reacted with 20 ml. of acetyl chloride in ether suspension to give, upon evaporation of the volatiles, 1-acetyl-3-isopropylpyrazolo[3,4-a]inden-4(1H)-one. In similar fashion the sodium salt (20 g.) is reacted with 15 ml. of benzoyl chloride to give l-benzoyl-S-isopropylpyrazolo- [3,4-a]inden-4(lH)-one. Both of these ketones are reacted with excess hydrazine to form the respective hydrazones as in Example 1.

To a mixture of 3.5 g. of 1-acetyl-3-isopropylpyrazolo- [3,4-a]inden-4-(1H)-one, hydrazone and 25 ml. of acetone is added 3 drops of concentrated hydrochloric acid. After five minutes the excess acetone is removed in vacuo and the residue is recrystallized from aqueous methanol to give 1-acetyl-3-isopropylpyrazolo[3,4-a]im den-4(1H)-one, acetone azine.

Concentrated hydrochloric acid (2 drops) is added to a mixture of 1.8 g. of 1-benzoyl-3-isopropylpyrazolo- [3,4-a]inden-4(1H)-0ne, hydrazone and 15 ml. of acetone. Working up as described above for the l-acetyl compound gives 1-benzoy1-3-isopropylpyrazolo[3,4-a]- inden-4(lH)-one, acetone azine.

Example 3 To a suspension of 2.0 g. of 3-isopropylpyrazolo[3,4-a1- inden-4(1H)-one, hydrazone, made as in Example 1, in 10 ml. of 1,1,l-trifiuoro-2-propanone is added 2 drops of concentrated hydrochloric acid in 5 m1. of ether keeping the suspension in an ice bath. After 15 minutes, the suspension is diluted with water and filtered. The solid is recrystallized from aqueous methanol to give 3-isopropylpyrazolo[3,4-a]inden-4 (1H) one, 1,1,l-trifluoro-2-propanone azine, M.P. 159162 C.

Example 4 A suspension of 5.7 g. of 3-isopropylpyrazolo[3,4-a]- inden-4(1H)-one, hydrazone, made as in Example 1, in 6 ml. of 98% formic acid and 50 ml. of: methanol is treated with 18 ml. of 37% formaldehyde .in aqueous methanol. The resulting mixture was heated at about 50 C. for 15 minutes. Concentration of the mixture and recrystallization of the residue from aqueous ethanol gives 3-isopropylpyrazolo[3,4-a]inden 4( 1H) one, formaldehyde azine, M.P. 155-158" C.

Example 5 A mixture of molar equivalent quantities of dimethyl 4-acetoxyphthalate and methyl ethyl ketone in benzene with a sodium hydride suspension condensing agent is reacted and worked up as in Example 1 to give crude Z-propionyl 5 acetoxy 1,3 indandione. This solid is slurried with 15% aqueous hydrochloric acid to remove the O-acetyl group. Recrystallization of the resulting solid from aqueous ethanol gives 2-propionyl-5-hydroxy- 1,3-indandione.

A mixture of 3.2 g. of 2-propionyl 5 hydroxy 1,3- indandione, prepared as above, and 12.0 g. of anhydrous hydrazine in 200 m1. of anhydrous benzene is heated at reflux for 18 hours. The resulting solid is a mixture of isomers, 3-ethyl-6-hydroxypyrazolo[3,4-a1- inden-4(1H)-one, hydrazone and 3 ethyl 7 hydroxypyrazolo-[3,4-a)inden-4(1H)-one, hydrazone which are separated by fractional crystallization from aqueous ethanol.

To 1.5 g. of 3-ethyl-6-hydroxypyrazolo[3,4-a1inden- 4(1H)-one, hydrazone in 20 ml. of acetone is added 2 drops of concentrated hydrochloric acid. After ten minutes, the solution is concentrated in vacuo and the residue is recrystallized from aqueous ethanol to give 3-ethyl-6 hydroxypyrazolo[3,4-a]inden-4(1H)-one, acetone azine.

Similarly treating a mixture of 1.0 g. of 3-ethyl-7-hydroxypyrazolo[3,4-a]inden-4 (1H)-one, hydrazone and 15 ml. of acetone with 2 drops of hydrochloric acid gives, after concentrating the solution and recrystallizing the Example 6 A solution of 1.8 g. of 2-acetyl-1,3-indandione and 0.5 g. of hydrazine hydrate in ethanol is heated at reflux for 1 hour. Quenching the reaction mixture gives a solid, 3-methylpyrazolo [3 ,4-a] inden-4( 1H) -one.

This compound (1.8 g.) is reacted with 0.75 g. of hydrazine in methanol for 16 hours to give the 4-hydrazone, M.P. 250-255 C.

Concentrated hydrochloric acid (2 drops) is added to a mixture of 1.2 g. of 3-methylpyrazolo[3,4-a]inden- 4( 1H)-one, hydrazone and 10 ml. of Z-butanone. After ten minutes, the excess ketone is removed in vacuo and the residue is recrystallized from aqueous methanol to give 3-methylpyrazol0[3,4-a]inden 4(1H) one, 2-butanone azine.

Example 7 A mixture of 2.5 g. of 3-(3-butenyl)-pyrazol0[3,4-a]- inden-4(1H)-one, hydrazone, prepared by condensing dimethyl phthalate with -hexen-2-one and reacting the thus formed 2 (4 pentenoyl) 1,3 indandione with two equivalents of hydrazine as in Example 1, and 20 ml. of acetone is treated with 3 drops of concentrated hydrochloric acid. Removal of the excess acetone in vacuo and recrystallization of the residue from aqueous ethanol gives 3-(3-butenyl)-pyrazolo[3,4-a]inden-4(1H) one, acetone azine.

Example 9 To a mixture of 3.0 g. of 3-t butyl-7-trifluoromethylpyrazolo[3,4-a]inden-4(1H)-one, hydrazone (prepared as described in copending application, Serial No. 848,927, filed October 27, 1959, now Patent No. 2,969,- 373, of January 24, 1961, and 25 ml. of acetone is added 3 drops of concentrated hydrochloric acid. Removal of the excess acetone in vacuo and recrystallization of.

the residue from aqueous methanol gives 3-t-butyl-7-trifluoromethylpyrazolo[3,4 aJinden 4(1H) one acetone azine.

xample 10 A mixture of 2.0 g. of 3-n-hexylpyrazolo[3,4-a]-inden- 4(1H)-one, hydrazone (prepared by the procedure of Example 1, condensing dimethyl phthalate with 2-octanone and reacting the resulting 2-n-heptylyl-1,3-indandione with hydrazine) and 5 ml. of 98% formic acid in 35 ml. of methanol is treated With 10 ml. of 37% formaldehyde. After heating at 50 C. for minutes, concentrating the mixture and recrystallizing the residue from aqueous ethanol 3-n-hexylpyrazolo [3,4-a]inden-4(1H)- one, formaldehyde azine is obtained.

Example 11 A mixture of 1.5 g. of 3-benzyl-5,6,7,8-tetrachloropyrazolo[3,4-a]inden 4(1H) one, hydrazone (prepared by condensing methyl benzyl ketone with dimethyl tetrachlorophthalate and reacting the resulting 2-phenylacetyl-4,5,6,7-tetrachloro-1,3-indandione with two equivalents of hydrazine) and 5 ml. of 98% formic acid in methanol is treated with 8 ml. of 37% formaldehyde.

6 The resulting mixture is heated at 50 C. for 15 minutes. Working up as in Example 10 gives 3-benzyl-5,6,7,8- tetrachloropyrazolo[3,4-a1inden 4(1H) one, formaldehyde azine.

Example 12 A mixture of 97.0 g. of dimethyl phthalate and 42.0 g. of cyclopropyl methyl ketone is treated with 28.5 g. of sodium methoxide and 300 ml. of toluene. After heating on the steam bath for ten hours and working up as in Example 1, 2-cyclopropylcarbonyl-1,3-indandione, M.P. 130132 C. is obtained.

A mixture of 21.4 g. of the indandione, 5.0 g. of hydrazine hydrate and 250 ml. of ethanol is refluxed for live hours. Cooling, adding water, filtering and recrystallizing the resulting solid from aqueous ethanol gives 3- cyclopropylpyrazolo[3,4 -a]inden 4(1H) one, M.P. 212-219 C.

A mixture of 21.4 g. of 2-eyclopropylcarbonyl-1,3- indandione, 8.5 .g. of hydrazine and 200 ml. of ethanol is refluxed for 48 hours. Cooling separates 3- cyclopropylpyrazolo[3,4-a]inden-4(1H) one, hydrazone, M.P. 247-251 C. I

To a suspension of 2.5 g. of this hydrazone and 20 ml. of acetone is added 2 drops of concentrated hydrochloric acid. After standing for five minutes, the solution is concentrated and the residue is recrystallized from aqueous methanol to give 3-cyclopropylpyrazolo[3,4-a]- inden-4(1H)-one, acetone azine.

Example 13 A mixture of 3.5 g. of 3-cyclopropylpyrazolo[3,4-a]- inden-4(1H)-one, prepared as in Example 12, and ml. of 10% aqueous sodium hydroxide is warmed for 3 minutes. The sodium salt is separated by filtration. A mixture of 0.5 g. of the sodium salt and 1 ml. of ethyl chloroformate in 10 ml. of ethanol is heated at reflux [for 15 minutes. The volatiles are removed to leave 1- carbethoxy-3 cyclopropylpyrazolo[3,4-a]inden 4(1H)- one. A mixture of this ketone, 0.5 g. oat hydrazine and 100 ml. of ethanol is refluxed for 16 hours. 'The solution is filtered to give l-carbethoxy 3 cyclopropylpyrazolo[3,4-a]inden-4(1H)-one, hydrazone. I

Concentrated hydrochloric acid (2 drops) is added to a mixture of 2.0 g. of the above prepared hydrazone and 20 ml. of acetone. Evaporating the excess acetone and recrystallizing the residue gives 1-carbethoxy-3-cyclopropylpyrazolo[3,4 a]inden-4(1H)-one, acetone azine.

- In similar fashion, a mixture of 0.5 g. of the sodium salt prepared above and 0.4 g. of methyl chloroformate' in 25 m1. of ether is refluxed for 15 minutes and concentrated to give 1carbomethoxy-3cyclopropylpyrazo-lo- [3,4-a]inden-4(1H)-one. This crude ketone is reacted with an excess of hydrazine in ethanol to separate the corresponding 4hydrazone. Treatment of a mixture of this hydrazone and 10 ml. of acetone with two drops of concentrated hydrochloric acid gives 1-carbomethoxy-3- cyclopropylpyrazolo[3,4 a]inden 4(1H) one, acetone azine.

Example 14 A mixture of 2.5 g. of 3-cyclopropylpyrazolo[3,4-a]- inden-4(1H)-one, made as in Example 12, and 75 m1. of 10% aqueous sodium hydroxide is warmed very briefly, then concentrated to a small volume. The sodium salt is isolated by filtration. A mixture of 1.5 g. of this salt and 5.0 g. of methyl iodide in 25 ml. of ethanol is heated at reflux for 5 hours. The volatiles are removed to leave 3-cyclopropyl-1 methylpyrazolo[3,4 a]inden- 4(1H)-one. This ketone is heated with 1.0 g. of hydrazine in 100 ml. of methanol for 48 hours to separate the 4-hydrazone of the 1-methyl compound.

To a mixture of 1.5 g. of 3-cyclopropyl-1-methylpyrazolo[3,4-a]inden-4(1H)-one, hydrazone and 15 m1. of acetone is added 3 drops of concentrated sulfuric acid. After ten minutes, the solution is concentrated and the 7 residue is recrystallized from aqueous methanol to give 3-cyclopropyl 1 methylpyrazolo{3,4 a]'inden 4(1H)'- one, acetone azine.

Similarly the sodium salt (1.0 g.) prepared above is reacted with 8.0 g. of butyl bromide in ethanol solution to give 1.-butyl-3-cyclopropylpyrazolo[3,4 a]iden 4(1H)- one. This compound is reacted with an excess of. hydrazine (1.0 g.) in ethanol at reflux for 48 hours to give 1-butyl-3-cyclopropylpyrazolo[3,4-a1inden 4(1H) one, hydrazone. Treatment of a mixture of this hydrazone and 10 ml. of acetone With 2 drops of concentrated hydrochloric acid furnishes l-butyl-icyclopropylpyrazolo- [3,4-a]inden-4(1H)-one, acetone azine.

Example 15 A solutiont of 5.1 g. of 2-cyclol'1exylcarbonyl-1,3- indandione, MP. 77 C. and 0.65 g. of hydrazine in 250 ml. of methanol is heated at reflux for six hours to give, after isolation as in Example 12, 3-cyclohexylpyrazolo- [3,4-a]inden-4(1H)-one. The hydrazone derivative of this ketone is prepared by heating with one equivalent of hydrazine in ethanol for 24 hours.

A mixture of 3.0 g. of 3-cyclohexy1pyrazolo[3,4-a1- inden-4(1H)-one, hydrazone and 15 g. of cyclopropyl methyl ketone in 30 ml. of ether is treated with 2 drops of concentrated hydrochloric acid. After heating at 50 C. for 15 minutes, water is added. The solid is isolated by filtration and recrystallized from aqueous methanol to give 3-cyclohexylpyrazolo[3,4 -a]'inden-4(1H) one, cyclopropyl methyl ketone azine.

Example 16 Cyclohexyl methyl ketone (10 g.) and 2.0 g, of 3-- vinylpyrazolo [3,4-a]inden-4( 1H) -one, hydrazone (prepared by condensing dimethyl phthalate with 3'-buten-2- one and treating the product with 2 equivalents of hydrazine) are treated with 2 drops of concentrated hydrochloric acid in 10 ml. of ether. Heating for 15' minutes, adding water and filtering and recrystallizing the solid gives 3-vinylpyrazolo[3,4-a]inden-4(1H)-one, cyclohexyl methyl ketone azine.

Example 17 A mixture of 2.4 g. of 2-(1-cyclopenten-1-ylcarbonyl)- 1,3indandione, prepared by condensing diethyl phthalate with l-cyclopenten-i-yl methyl ketone, and 1.5 g. of hydrazine hydrate in 200 ml. of methanol is heated at reflux for 48 hours. The resulting, solid is 3-(1-cyclopenten-l-yl)pyrazolo[3,4-a]inden-4(1H) one, hydrazone. Treatment of this hydrazone and. 25 ml. of nonanone' with 3 drops of concentrated hydrochloric acid and working up as in Exampie 15 gives 3-(1-cyclopenten- I-yDpyrazolo[3,4-a]inden-4(1H)-one, 5-nonanone azine.

Example 18 A mixture of 2.5 g. of 2-(1,3-cyclohexadien-1-ylcarbonyl)-1,3-indandione, prepared by condensing 1,3-cyclohexadien-l-yl methyl ketone with dimethyl phthalate, and 0.5 g. of hydrazine hydrate in 150 ml. of ethanol is re.- fluxed for 20 hours to give, ter quenching With cold Water, 3- 1,3-cyclohexadien-1-yl)pyrazolo [3 ,4-a] inden-4- (1H)-one. This ketcne is heated at reflux with 1.0 g. of hydrazine hydrate and 100 ml. of ethanol for 20 hours to give, upon cooling and filtering, 3(1,3-cyclohexadien-1- yl pyrazolo 3,4-a] inden-4( 1H) -one, hydrazone.

To a mixture of 2.0g. of this hydrazone and g. of methyl benzyl ketone is added 2 drops. of concentrated hydrochloric acid. at room temperature, water is added and thesolid is separated by filtration. Recrystallization from aqueous methanol gives 3-(1,S-cyclbhexadien-1-yl)pyrazolo[3,4- a] inden-4(lH)-one, methyl bcnzyl ketone azine.

Example 19 A mixture of 4.0 g. of 3-isopropylpyrazolo[3,4-a]inden-- 4(1H)-one, hydrazone, made as in Examplel, and.6.0.

After standing for minutes g. of ben'zaldehyde is treated with 3 drops of concentrated hydrochloric acid. After heating for ten minutes at 45 C., the solution is diluted with water. The solid is filtered and recrystallized from aqueous methanol to yield 3-isopropylpyrazolo [3,4-a [inden-4(1H) one, benzaldehyde azme.

Example 20 Treating a mixture of 1.5 g. of 3-isopropylpyrazolo[3,4- a]inden-4(lH)-one, hydrazone, made as in Example 1, and 5.0 g. of p-chloroacetophenone with 2. drops of concentrated hydrochloric acid, heating at 45 C. for ten minutes and working up as in Example 19 yields 3-isopropylpyrazolo[3,4-a]inden-4(1H) one, p-chloroacetophenone azine.

Example 21 Two drops of concentrated hydrochloric acid is added to a mixture of 10.0 g. of m-methylacetophenone" and 4.0 g. of 3-isopropylpyrazolo[3,4 a]inden-4(1H)-one, hydrazone, prepared as in Example 1. After ten minutes, water is added. The solid which separates is 3-isopropylpyrazolo[3,4-a]inden-4(1H)-one, m-methylacetophenone azine.

Example 22 Condensation of dimethyl 3-ethoxy-4methoxy-phthalate with cyclopropyl methyl ketone in toluene solution containing sodium methoxide as in Example 1 gives2- cyclopropylcarbonyl 4-ethoxy-5 methoxy-1,3-indandione.

A mixture of 2.9 g. of the indandione, 1.5 g. of hydrazine and 200 ml'. of ethanol is heated at reflux for 72 hours. Cooling and filtration of the reaction mixture gives a mixture of 3-cyclopropyl-5-ethoxy-6-methoxypyrazolo[3,4-a]inden-4(1H)-one, hydrazone and 3-cyclopropyl-8-ethoxy-7-methoxypyrazolof3,4-a]inden 4(1H)- one, hydrazone.

These ketones are mixed with 8.0 g. of p-aminobenzaldehyde and the resulting mixture is treated with 3 drops of concentrated hydrochloric acid. After 10 minutes, water is added and. the: solid is filtered off to give a mixture of isomers 3-cyclopropyl-5-ethoxy-o-methoxyp-yrazolo- [3,4'a]inden-4(1H)-one, p-aminobenzaldehyde azine and 3-cyclopropyl-8-ethoxy-7 methoxypyrazolo[3,4-a]inden- 4(1H)-one, p-aminobenzaldehyde azine which are separated by fractional crystallization from aqueous ethanol.

Example 23 A mixture of 3.5 g. of 3-isopropyl-8-trifluoromethylpyrazolo[3,4-a]inden-4(1H)-one, hydrazone, made as described in copending application Serial No. 848,927, filed October 27, 1959, now Patent No. 2,969,373 of January 24, 1961, and 6.0 g. of p-methoxyacetophenone is treated with 2 drops of concentrated hydrochloric acid. Working up as in Example 22 gives 3-isopropyl-S-trifluoromethylpyrazolo[3,4-a]inden-4(1H)-one, p methoxyacetophenone azine.

Similarly adding hydrochloric acid to a mixture of 3- isopropyl-S-trifluoromethylpyrazolo 3 ,4a] inden 4 1H) one, hydrazone, prepared as described in copending application Serial No. 848,927, filed October 27, 1959, now Patent No. 2,969,373 of January 24, 1961, and o-ethoxybenzaldehyde gives 3-isopropyl-5-trifluoromethylpyrazolo- [3,4-a]inden-4(lI-I)-one, o-ethoxybenzaldehyde azine.

Example 24 A mixture of 3.1 g. of 5bromo-2isovaleryl-1,3-indandione and 0.5 g. of hydrazine hydrate in 200 ml. of ethanol is heated at reflux for 3 hours. The solution is quenched to yield monooromo-3-iscbutylpyrazolo[3,4- a]-inden-4(1H)-one.

This crude ketone (2.7 g.) is reacted with an excess of hydrazine (2 g.) in methanol at reflux for 24 hours to give a mixture of 6-bromo-3-isobutylpyrazolo[3,4-a]inden-4(1H)-one, hydrazone and. 7-bromo-3risobutylpyrazolo[3,4-a]inden-4(1H)-one, hydrazone.

Treatment. of these hydrazoneswithexcess o-bromo 9. benzaldehyde and concentrated hydrochloricacid gives 6(and 7)-brorno-3-isobutylpyrazolo[3,4-a]inden 4(1H) one, o-brornobenzaldehyde azine which are separated by fractional crystallization from ethanol.

Example 25 A mixture of 19.4 g. of dimethyl phthalate, 5.7 g. of sodium methoxide, 10.8 g. of cyclobutyl methyl ketone and 100 ml. of benzene is reacted as in Example 1 to give the solid 2-cyclobutylcarbonyl-1,3-indandione.

Heating 2.3 g. of the dione, 1.0 g. of hydrazine and 100 ml. of ethanol at reflux for 17 hours and cooling the solution separates 3-cyclobutylpyrazolo[3,4a]inden-4- (1H)-one, hydrazone. I

To a mixture of 1.5 g. of the hydrazone and 6.5 g. of hydrocinnamaldehyde is added 2 drops of concentrated hydrochloric acid. After heating for ten minutes at 50 C., the solution is cooled and diluted with water. Filtration and recrystallization of the solid from ethanol gives 3-cyclobutylpyrazolo[3,4-a]inden-4(1H)-one, hydrocinnamaldehyde azine.

Example 26 Hydrazine (0.5 g.) and 2.4 g. of 2-cyclopropylcarbonyl-5,6-dimethyl-1,3-indandione, prepared by condensing dimethyl 4,5-dimethylphthalate with cyclopropyl methyl ketone, are reacted as'in Example 12 to give 3-cyclopropyl-6,7 dimethylpyrazolo [3,4-a] inden-4( 1H) one.

A mixture of 1.2 g. of the above prepared ketone, 0.2 g. of hydrazine and 100 ml. of methanol is heated at reflux for 48 hours. Cooling separates 3-cyclopropyl-6,7- dimethylpyrazolo[3,4-a]inden-4(1H)-one, hydrazone.

A mixture of 1.0 g. of this hydrazone-and 4'ml. of

98% formic acid in 20 ml. of methanol is treated with ml. of 37% formaldehyde in methanol-water. The

mixture is heated at 50 C. for minutes and concentrated in vacuo. The residue is recrystallized from aqueous ethanol to give 3-cyclopropyl-6,7-dimethylpyrazolo [3,4-a] inden-4( 1H) -one, formaldehyde azine.

Example 27 to a mixture of 5.0 g. of 6-chlor0-3-isopropylpyrazolo- [3,4-a]inden-4(1H)-one, hydrazone and ml. of a'cetaldehyde in ether solution. After ten minutes, water is added and the solid is'separated by filtration and recrystallization from aqueous methanol to give 6-chloro-3-isopropylpyrazolo[3,4 a]inden 4(1H) one, acetaldehyde azine.

Similarly treating a mixture of 7-chloro-3-isopropylpyrazolo[3,4-a]inden-4(1H)-one, hydrazone and acetaldehyde in ether solution with concentrated hydrochloric acid yields 7-chloro- 3 -isopropylpyrazolo[3,4-a]inden- 4(1H)-one, acetaldehyde azine.

Example: 28

A mixture of 1.0 g. of 6(and 7)-chloro-3-isopropylpyrazolo[3,4-a]inden-4(lH)-one, prepared as in Example 27, is converted to the potassium salt'by heating with 50 ml. of 5% potassium hydroxide. The resulting potassium salt is refluxed with 0.8 g. of benzenesulfonyl chloride and 30 ml. of ether for ten minutes. Evaporation of the reaction mixture leaves, as the residue, a mixture of isomers -1-.benzenesulfonyl-6(and '7)-chloro-3-isopropyl-' pyrazolo[3,4-a]inden-4(1H)-one. Reaction of these ketones with excess hydrazine in ethanol gives the corresponding 4-hydrazones which are separated by fractional crystallization from ethanol to give l-benzenesulfonyl- 6 chloro 3 isopropylpyrazolo[3,4 a]inden 4(1H)- one, hydrazone and 1-benzenesulfonyl-7-chloro-3-isopropylpyrazolo[3,4-a] inden-4( 1H) -one, hydrazone.

To a mixture of 1.2 g. of 1-benzenesulfonyl-7-chloro- 3-isopropylpyrazolo[3,4-a]inden-4( 1H)-one, hydrazone and 10 ml of acetone is added 2 drops of concentrated hydrochloric acid. After five minutes, the excess acetone is removed in vacuo and the residue is recrystallized from aqueous methanol to give 1-benzenesu1fonyl-7- chloro-3-isopropylpyrazolo[3,4-a]inden-4( 1H)-one, acetone azine.

Similarly by reacting l-benzenesulfonyl-G-chloro-3-isopropylpyrazolo[3,4-a] inden-4( 1H)-one, hydrazone with acetone in the presence of hydrochloric acid l-benzenesulfonyl 6 -chloro 3 isopropylpyrazolo[3,4 a]inden 4(1H)-one, acetone azine is obtained.

Example 29 A mixture of 5(and 8)-chloro-3-isopropylpyrazolo [3,4-a]inden-4(1H)-one (made by condensing 3-methyl- 2-butanone with dimethyl 3-chlorophthalate and reacting the thus formed 2-isobutyryl-4-chloro-1,3-indandione with hydrazine) and one equivalent of hydrazine is refluxed for 36 hours in ethanol to give a mixture of the corresponding 4-hydrazones which are separated by fractional crystallization from ethanol.

Treating a mixture of 1.0 g. of 5-chloro-3-isopropylpyrazolo[3,4-a]inden-4(1H)-one, hydrazone and 15 ml.

of acetone with 2 drops of hydrochloric acid and working up the reaction mixture as in Example 28 gives 5- chloro 3 isopropylpyrazo1o[3,4 a]inden 4(1H)- one, acetone azine. v p

Adding 2 drops of concentrated hydrochloric acid to a mixture of 1.5 g. of 8-chloro-3-isopropylpyrazolo[3,4- a]inden-4(1H)-one, hydrazone and 15 ml. of 3-pentanone, heating at 50 C. for ten minutes, cooling, diluting with water, and filtering gives 8rchloro-3-isopropylpyrazolo [3,4.-a]inden-4(1H)-one, 3-pentanone' azine.

Example 30 Example 31 A solution of 1.0 g. of 3-cyclopropylpyrazolo[3,4-a]- inden-4(1H)-one, made as in Example 12, in ml. of ether-te'trahydrofuran is reacted with an equivalent amount of potassium amide. tered off and reacted with an excess of benzyl chloride inethanol to form 1-benzyl-3-cyclopropylpyrazolo [3,4-a] inden-4(1H)-one.

Reaction of the above prepared ketone with excess hydrazine furnishes the corresponding hydrazone.

Treatment of a mixture of 1.0 g. of l-benzyl-3-cyclopropylpyrazolo[3,4-a]inden-4(1H)-one, hydrazone and 10 ml. of acetone with 2 drops of concentrated hydrochloric acid and working up as in Example 30 gives 1- benzyl 3 cyclopropylpyrazolo[3,4-a]inden-4(1H)-one, acetone azine.

Similarly the potassium salt prepared above is reacted with an excess of phenethyl chloride in ethanol to form 3-cyclopropyl-1-phenethylpyrazolo[3,4-a]inden 4(1H)- one. Reaction of this ketone. with hydrazine by reflux:

The potassium salt is fil- 11 ing in ethanol for 20 hours yields 3-cyclopropy1-1-phenethylpyrazolo[3,4-a]inden-4(1H)-one, hydrazone. This hydrazone (1.0 g.) is reacted with 8 ml. of p-ethylace'tophenone in the presence of 2 drops of hydrochloric acid to give 3-cyclopropyl-l-phenethylpyrazolo[3,4-a1inden- 4(1H)-0ne, p-ethylacetophenone azine.

Example 32 A mixture of 3.8 g. of 2-('6-hepteno=yl)-5-iodo-1,3-indandione, prepared by condensing dimethyl 4-iodophthalate with S-hexene methyl ketone, and 0.7 g. of hydrazene in 150 ml. of ethanol is heated at reflux for 24 hours to form a mixture of 3-(5-hexenyl)-6-iodopyrazolo- [3,4-a]ind'en'-4( lH)-one, hydrazone and the corresponding 7-iodo isomer. Separation of these isomers is accomplished by fractional crystallization from ethanol.

To a mixture'of 1.8 g. of S-(S-hexenyl)-6-iodopyrazolo- [3,4-a]inden-4(1H)-one, hydrazone and 20 ml. of acetone is added 2 drops of concentrated hydrochloric acid. Evaporation of the excess acetone and recrystallization of the residue gives 3-(5-hexenyl)-6-iodopyrazolo[3,4-a]'- inden-4(1H)-one, acetone azine.

Example 33 A mixture of 2.6 g. of 2-butyryl-5-nitro-1,3-indandione, prepared by condensing dimethyl 4-nitrophthalate with 2-pentanone, and 0.32 g; of hydrazine is heated at reflux in ethanol for five hours to form a mixture of 6-nitro-3- n-propylpyrazolo[3,4-a]inden 4(lH)-one and the corresponding 7-nitro compound. Treatment of these ketones with excess hydrazines gives the corresponding 4-hydrazones which are separated by fractional crystallization.

To a mixture of 1.0 g. of 6-nitro-3-n-propylpyrazolo- [3,4-a]inden-4(1H)-one, hydrazone and 15 ml. of acetaldehyde in either solution is added 2 drops of concentrated hydrochloric acid. Working up as in Example 27 gives 6-nitro 3 n propylpyrazolo[3,4-a]inden- 4(1H)-one, acetaldehyde azine.

Example 34 A mixture of3.0 g. of 3=n-propyl-7(and 6)-nitroindeno- (1',2 -c)pyrazol-4-one, prepared as in Example 33, in ml. of pyridine and a solution of 3 equivalents of sodium hydrosulfite in 10 ml. of water is heated at reflux for about 30 minutes. The mixture is quenched and extracted to give the solid 6(and 7)-amino-3-n-propylpyrazolo[3,4-a]inden-4(1H)-one. This crude material is dissolved in 100 ml. of ethanol and heated at reflux with 1.1 equivalents of hydrazine for 4 hours to form the corresponding 4-hydrazones which are separated by-fractional crystallization from ethanol.

Treatment of a mixture of 1.2 g. of 7-amino-3-npropylpyrazolo[3,4-a]inden-4(1H)-one, hydrazone and ml. of acetone with 2 drops of concentrated hydrochloric acid as in Example 32 yields 7-amino-3-n-propylpyrazolo[3,4-a]inden-4('1H)-one, ace-tone azine.

Example 35 A mixture of. 6.8 g. of. 4bromo-2-cyclopropylcarbonyl- S-hydr'oxy-G-methoxy-l,S-indandione (prepared by condensing dimethyl 3-bromo-4-acetoxy-S-methoxyphthalate with cyclopropyl methyl. ketone), 0.7 g. of hydrazine and 300 ml. of ethanol is refluxed for six hours to give, after cooling, diluting with water andfiltering, a mixture of 5- bromo-3-cyclopropyl 6 hydroxy-7-methoxypyrazolo- [3,4-a]inden 4(lH).-one and- 8-hromo-3-cyclo1aropyl-7- hydroxy-fi' methoxypyrazolo [3,4-a] inden-4( 1H -one. The hydrazone. derivatives of these ketones are prepared by heating with one equivalent of hydrazinein ethanol for 24 hours. Separation of these isomers is accomplished by fractional crystallization from aqueous ethanol.

Concentrated hydrochloric acid (3 drops) is added to a mixture of 4.0g. of5-bromo-3-cyclopropyl-6-hydroxy- 7-methoxypyrazolo.[3,4-a} inden-.4( 1H) one, hydrazone and 2.5 ml. of. acetone.- After 15 minutes the excess acetone is evaporated in vacuo and the residue is recrystallized from methanol to give S-bromo-3-cyclopropyl-6- hydroxy 7 methoxypyrazolo[3,4-a]inden 4(1H)-one, acetone azine.

Example 36 The sodium salt of 3-isopropylpyrazolo[3,4-a]inden- 4(1H)-one (1.5 g.), prepared as in Example 2, is refluxed with 10 ml. of propionyl chloride in ether solution to give, upon concentration of the solution, 3-isopropyl- 1-propionylpyrazolo[3,4 a] inden-4( 1H) -one. Reaction of this ketone with excess hydrazine in ethanol gives the hydrazone derivative.

Treating a mixture of 1.2 g. of the above prepared hydrazone and 20 ml. of 2-pentauone with 2 drops of concentrated hydrochloric acid and working up as in Example 35 gives 3-isopropyl-l-propionylpyrazolo[3,4-a]- inden-4(1H)-one, 2-pentanone azine.

What is claimed is:

1. A chemical compound having the following forin which R is a member selected from the group consisting of alkyl having 1 to 6 carbon atoms inclusive, alkenyl having 2 to 6 carbon atoms inclusive, benzyl, phenethyl, cycloalkyl having 3 to 6 carbon atoms inclusive, and cycloalkenyl having 4 to 6 carbon atoms inclusive; R is a member selected from the group consisting of hydrogen, alkyl having 1 to 4 carbon atoms inclusive and trifiuoromethyl; R is a member selected from the group consisting of hydrogen, alkyl having 1 to 4 carbon atoms inclusive, trifluorome'thyl, cycloalkyl having 3 to 6 carbon atoms inclusive, phenyl, halophenyl, lower alkoxyphenyl, lower alkylphenyl, aminophenyl, benzyl and phenethyl; R is a member selected from the group consisting of hydrogen, chloro, bromo and iodo; R and R are members selected from the group consisting of hydrogen, chloro, bromo, iodo, lower alkyl, lower alkoxy, hydroxy, nitro, amino and tn'fluoromethyl; R is a member selected from the group consisting of hydrogen and, when the carbocyclic ring is tetrasubstituted, chloro, bromo and iodo and R is a member selected from the group consisting of hydrogen, alkyl having 1 to 4 carbon atoms, benzyl, phenethyl, benzenesulfonyl, benzoyl, acetyl, propionyl, carbethoxy and carbomethoxy.

121. A chemical compound having the following forrn a:

a Ra in which'R is alkylhaving 1- to 6 carbon atoms inclusive and R and R are alkyl'having 1 to 4 carbon atoms inelusive- 3. 3-isopropylpyrazolo[3,4-a]inden-4(1H)-one, acetone azme.

4. A chemical compound having the following forin which R is alkyl having 1 to 6 carbon atoms inclumula: sive and R, and R are alkyl having 1 to 4 carbon atoms H inclusive.

| 7. A chemical compound having the following for- 6 mula:

N 1%]! 10 R! C Y N R: R: IL in which R; is cycloalkyl having 3 to 6 carbon atoms in- 15 ll elusive and R and R are alkyl having 1 to 4 carbon atoms inclusive. R, RI

5. 3-cyclopropylpyrazo1o[3,4-a]indeu-4(1H)-one acetone azine. in which R, is alkenyl having 2 to 6 carbon atoms in- 6, A chemical compound having the following fore e and 2 and s are alkyl having 1 t 4 c r n mula: 20 atoms inclusive.

H 8. 3-(3-butenyl)-pyrazolo[3,4-a]inden-4(1H)one, acetone azine.

N W No references cited. 01

l JLR, 

1. A CHEMICAL COMPOUND HAVING THE FOLLOWING FORMULA: 